The goal of this proposal is to understand the molecular mechanism that governs conventional T (Tcon) cell resistance to regulatory T cell (Treg)-mediated suppression and identify potential molecular targets for use in immunotherapy. Research over the past decade has demonstrated that Treg cells are a crucial component for a healthy immune system. Once activated through their T cell receptor (TCR), Treg cells can suppress a wide range of immune cells. It is becoming evident that in many autoimmune diseases, Treg cells remain functional, yet fail to control Tcon cells. At the same time, Treg cell hinder anti-tumor immunity by creating a suppressive tumor microenvironment. Therefore, it is important to understand what determines if a Treg cell is able to successfully suppress its target, and how this plays a role in both autoimmune disease and cancer. My research focuses on the Src homology 2 domain- containing protein tyrosine phosphatase 1 (SHP-1), a well-characterized negative regulator of TCR-mediated signaling. Using three different genetic models of SHP-1 deficiency, I have recently found that SHP-1 regulates the susceptibility of Tcon cells to suppression, such that SHP-1-deficient Tcon cells display increased resistance to wt Treg-mediated suppression. In preliminary data, I have shown that Tcon cells derived from motheaten mice, which lack SHP-1 expression in all hematopoietic cells, are resistant to Treg-mediated suppression. I also observed a comparable resistance in Tcon cells from two different mouse models, carrying a T cell specific deletion of SHP-1, indicating that the SHP-1-dependent resistance to suppression is a T cell-intrinsic effect. Moreover, treatment of mice with sodium stibogluconate (SSG), a pharmacological SHP-1 inhibitor, also rendered Tcon cells resistant to Treg-mediated suppression, further reinforcing the role of SHP-1 in regulating Tcon cell susceptibility to Treg suppression. Interestingly, SSG is in phase I clinical trials for solid tumo immunotherapy, yet its anti-tumor mechanism remains unclear. The proposed study will shed light on how SSG might be augmenting Tcon cells' ability to resist Treg-mediated suppression and mount a more effective anti-tumor response. This proposal will address the role of SHP-1 in CD4+ and CD8+ T cell susceptibility to Treg mediated suppression both at the level of intracellular signaling pathways as well as in vivo in models of autoimmune disease, inflammation, and anti-tumor immunity. From these studies, I will identify possible molecular drug targets, the modulation of which would either induce Tcon cell susceptibility to Treg-suppression for treatment of autoimmune disease, or allow Tcon cells to resist Treg suppression for treatment of cancer.